Chemical substance



Patented July 9, 1929.

UNITED STATES ELMER H. KING, OF CAPE ELIZABETH, MAINE.

CHEMICAL SUBSTANCE.

N 0 Drawing.

The present invention is directed to new compounds and methods of makingthe same, said compounds being of particular utility in the treatment ofvarious human ailments. Perhaps the most important use is in thetreatment of those diseases of the body cells or tissues coming underthe general classification of sarcomata, carcinomata, glandularhypertrophies and chronic inflammation.

The compounds are in a colloid-like state, and according to the presentpreferred method are prepared by combining alkaloids with desaccharatedglucosides. The term desaccharated glucosides is intended to ineludesuch compounds as remain after splitting off sugar components ofglucosides by any suitable process.

The use of the compounds in the treatment of the diseases mentionedabove has demonstrated that the alkaloids are desirable because of theirspecificity and because of their heptaphoric property of binding orholding the desacch'arated glucosides; and the desaccharated glucosidesare employed because they are capable of performing the desired actionupon certain pathological cells, that is, for their toxophoric eftec Thecompositions of matter of the present invention comprise two elements orradicals, namely a toxophore, or toxic substance, and a heptaphore, orbinding substance, the heptaphore bein of such a nature that themolecules of the compositions of matter of the present invention aregenerally in an aggregated state, and by reason of the isocolloidalityof the compositions, the aggregated particles are capable of assumingdecreasing orders of magnitude with increasing dilution.

The toxophore may be desaccharated glucoside, but it may also be asubstance unrelated thereto, as for example, salvarsan, or othermetallo-organic compound, which may contain mercury, arsenic, sil er,etc.; while the heptaphore is generally an alkaloid or some compoundderived therefrom. The binding quality of the heptaphore is apparentlydue to the polymerization, or the colloidality, or as it may be termed,the isocolloidality, of the composition of matter of which it is aradical; and it is a function of the alkaloid V employed.

As far as known, it is new to combine alkaloids and desaccharatedglucosides, in fact heptaphores and toxophores. The dcsaccharatedglucosides act as acids and the alkaloids act as bases to form more orless Application filed February 2, 1922. Serial No, 533,671.

definite salts. It is also new to produce such salts in a colloid-likestate.

Preferably, the alkaloids employed are quinine, quinicine and caifein,and these may be used in various forms. For example, quinine has beenemployed as the alkaloid itself, as the hydrochloride, and as thedihydrochloride. Processes for making the compounds of this inventionfrom ingredients including these three forms of quinine, wherein thequinine is converted into the isomeric quinicine, are set forthhereinafter. Cinchonine, cinchonidine, and quinidine, and theirhydrochloric and sulphuric acids salts may also be employed, and ofthese the sulphates and disulphates are preferred. Emetin, and perhapsatropin and morphine, may be used as alkaloids in the preparation of thecompounds; and compounds containing a quinoline nucleus are ofparticular value. Quinine and quinidine, leevo-rotatory anddextro-rotatory respectively, are isomeric and are converted intoquinicine by boiling in water or in an aqueous acid solution, such, forexample, as acetic or hydrochloric acid. Cinchonine and cinchonidinewhich are isomers, are converted by similar methods into cinchonicinewhich is an active binding agent. Cupreine and cupreidine are likewiseconverted into functionally active binding substance. Other very usefulsubstances are: Cinchonicine, hydro- (or dihydro-) quinine, hydro-(ordihydro-) quinidine, hydro- (or dih vdro-) cinchonine, hydro- (ordihydro-) cinchonidine, hydro- (or dihydro-) quinicine, hydro- (ordihydro-) cinchonicine.

Among the desaccliarated glucosides which have been used may bementioned the phenolic coloring matters, and in particular those of theflavonal, anthocyan and dihydropyran groups. It may be stated that weakphenolic acids generally are of value and that very good results havebeen obtained from liematoxylin, brazilin, quercitin, vitexin, fisetinand the morin of fustic.

The compounds obtained from the substances mentioned above, theirderivatives, substitutes or homologues, have varying degrees ofe'fliciency for different purposes. Generally, however, it is preferredto use hematoxylin as the acid and quinicine as the base, since thecompounds resulting from combining these substances as a rule have thegreatest efiiciency. 1

For the purpose of disclosing the method of preparing the compounds ofthe present invention, three processes will be described,

the first employing alkaloid quinine as a reagent, the second quininehydrochloride and the third quinine .dihydrochloride.

First method.

1. Add a gram-molecular weight of desacoharated glucoside (for example,hematoxylin) to 10,000 mils boiling one-half normal hydrochloric acid,and continue the boil- To the boiling solution resulting from the abovestep add a gram-molecular weight ofqu'inine, and continue boiling forabout ,20 m ut s 3. Cool to about 20 C. and adjust the vol- ,ume to-10,000 mils.

{l The excess acid may be removed by diajlysis or other suitableprocess, such as neutralization with a solution of sodiumbicarbonate-and the desaccharated ,glucosjide itself may be used as theindicator.

5. Filter-through ordinary filter paper. 6. sterilize, by heating to 110C.

Second method.

1, Add a gram-molecular weight ofdes. aecharated glucoside (for example,hematoxylin) to 10,000 mils of boiling one-half normal hydrochloricacid.

- Add to a grain-molecular weight of quinine hydrochloride in saturatedaqueous solution, saturated aqueous solution of sodium bicar onat untileifervescence ceases- 3, Add boiling solution (2) to boiling solution(1)., noting that so ution (2) contains aprec'ipitate which should beadded along with the liquid, and boiled together for about ZOmimites 4.Cool to about 20 C. The volume should be adjusted to 10,000 mils.

5, Remove the excess of acid, filter and sterilize as in the firstexample.

Third method.

ing results in the production of quinicine,

and if desired, quinicine may be used as a starting material in myprocess.

Other methods may be used for the preparation of my material, as. oneexample of which the following is given:

1. About thirty (30) parts of a concentrated solution of hydrochloricacid (having a strength of about 30% to 33%) is mixed with about ninetyparts of water. This is merely a very convenient method of preparinghydrochloric acid solution of the desired strength and any other methodmay be used. This solution of hydrochloric acid is heated to boiling.

2. Twelve (12) grams of hematoxylin are gradually added to the abovementioned boiling solution of hydrochloric acid.

3. The vessel containing the resulting mass is then maintained at atemperature of 40 0., preferably in a thermostat, whereupon, after abouttwenty-four (24) hours, crystals of hematoxylin hydrochloride separate pout.

'These crystals are collected and the mother liquor may be discarded.

a. One mol of the alkaloid quinine is dissolved in carbon bisul-phide orother solvent of the alkaloid which is not miscible with water. Thecarbon bisulphide is used merely as a special solvent and theamountthereof is more or less immaterial. By way of a specific example,however, it may be stated that a small excess of carbon bisulphide overthe amount necessary to dissolve the stated quantity of alkaloid willproduce good resul-ts.

5. One mol of hematoxylin hydrochloride, produced as indicated above, isdissolved in water. Here, also, the water is used merely as a solvent,and the amount thereof used is more or less immaterial, but by way ofspecific example it may be stated that a slight excess over the amountnecessary to dissolve the given quantity of hematoxylin hydrochloridewill produce good results.

6. The solution of alkaloid in carbon bisulphide and the solution ofhematoxylin hydrochloride in water are brought into con tact with eachother, preferably with stirring, on standing, an interface will beformed between the two solutions as they are immiscible, the aqueoussolution being supernatant. Crystals of quinine hematoxylinate areformed at this interface and drop into the carbon bisulphide layer.These crystals may be removed as rapidly as they are formed, provisionbeing made for the renewal of quinine in the carbon bisulphidc or othersolvent therefor used, and also for the renewal of hematoxylinhydrochloride in the water or other solvent therefor used.

' The solutions obtained by practicing the above processes are in acolloid-like state and may be used hypodermically in the treatment ofthe diseases. The hematoxylinates of the members of the cinchona groupand possibly other alkaloids are barely soluble in water, while suchhematoxylinates are more soluble and therefore can be made available ina more concentrated colloidlike condition if there is another acidicradical attached to a basic valence of the alkaloidal radical. For

this reason I often prefer to use a hydrochloride or other salt of thealkaloid; and when ever the compound, consist-ing merely of the alkaloidradical and the desaccharated glucoside radical, is too insoluble, Iprefer a compound having an additional acid radical attached to thealkaloid radical. A great many alkaloids have two amino groups, and asthe desaccharated glucoside generally attaches itselftooneof these aminogroups, it is possible to increase the solubility and the concentrationof the compound in a colloid-like solution by adding a hydrochloric orother acid radical to the compound, which acid radical apparentlyattaches itself to the other amino group.' Mixtures of differentsolutions, containing various alkaloids and desaccharated glucosides,may be employed in accordance with the diseases to be treated.

Caffein or its corresponding salt may be substituted for the quinine oreither of its hydrochlorides in the above processes. In accordance withthe effect desired the caffein products may be used alone 01' admixedwith the quinine (or quinicine) products in varying proportions.Preferably quinicine is employed as the alkaloid and hematoxylin as thedesaccharated glucoside. although the other alkaloids and desa-ccharatedglucosides give good results. Theobromine compounds are almost but notquite equal to the corresponding caffein compounds.

Slight immaterial changes can be made in a side chain of hematoxylineither by addition, subtraction or substitution without affecting itsaction to any great extent, and the same is more or less true of variousother materials mentioned herein.

Quinine, or rather its derivatives, is best suited for preparing thesalt to be used for the treatment of undifferentiated protoplasm andcalfein is best for differentiated. Hence quinine, or its derivatives,is best for the majority of the sarcoma-ta; while some require bothquinine and caffeinhematoxylinate. Most of the cancers require admixtureof both, in relative proportions approximately determinable by judgmentof how much of them is made up of differentiated (epithelial) tissue,and of how much undifferentiated li brous) tissue. A skilledpractitioner can determine within very close limits what shall be usedfor the majority of the sarcomata- (the remaining sarcomata, fairlyeasily recognized, belonging, so far as treatment goes, with thecarcinomata), what shall be used in cancers, what in pure glandular(epithelial) hypertrophies, and what in chronic inflammations.

The products are to be bottled ready for use, as they are fairly stableand have been kept in sealed glass containers for six months and foundefficient.

It is important to note that the efficiency of the products is more orless proportional to the lability of the hydrogen ions and that theproblem is to hold a delicate substance in unstable equilibrium untilthe patient receives it.

Investigations indicate that the preferred preparation is a new definitechemical substance in solution, viz: quinine-hematoxylinate, or rather,quinicine-hematoxylinate. This substance is, however, so delicate thatin the process of its isolation, oxidation occurs, resulting inquinicine-hei'natinate, which is incapable of reduction.

By employing the vvarious alternative substances as reagents newdefinite chemical compounds are obtained, all possessing to a greater orless degree the curative properties of the uinine-hematoxylinate, amongwhich may e mentioned, it being understood that the list is incomplete:quinine or quinicinebrazilinate, quinine or quinicine-quercetinate,quinine or quinicine-vitexinate, quinine or quinicine-quercitrinate,quinine or quinicinefisetinate, caffein-hematoxylinate,caffein-brazilinate, caffein-quercctinate, caffein-vitexinate,caffein-quercitrinate, caffeinfisetinate, morphin-fisetinate,morphin-hematoxylinate, atropin-morinate, atropin-hematoxylinate.

A probable theory of the action of the new compositions of matter isthat the mechanism of destruction of abnormal cells thereby consists oftwo phases, one physical and the other chemical. The physical phase isdue to the colloid-like nature of the compounds, and to the peculiarsurface activity of the abnormal cells resulting in adsorbing orincorporating colloid-like particles of the compounds which v consist ofa more or less large number of molecules into the cell bodies. After theadsorption or incorporation, depolymerization of the colloid-likeparticles begins; molecules of the substance are dispersed throughoutthe cell by the action of free water entering the cell; and afterdepolymerization, that is, assumption of the molecular disperse statethe chemical action begins, whereby the substance exerts its destructiveeffect on such cells. The dispersion is comparatively slow and gradual,as is the hydrolyzation, with the result that the colloid-like materialaffixed to the cells has the function of a reservoir for supplying areducing agent at the cell.

Although several compounds have been described and several methods forproducing the same, it is to be distinctly understood that the inventionis not limited to the particular compounds or methods recited, butincludes modifications and changes which come within the scope of theappended claims.

This application is a continuation in part of my application Serial No.374,904, filed April 19, 1920.

Having thus described the invention, what is claimed as new and desiredto be secured by Letters Patent is:

1. A medical composition of matter comprising the combination of aquinieine radical and a Weak phenolic acid radical.

2. A medical composition of matter comprising the combination of aquinicin-e radical and a radical of a member of the dihydropyran group.

3. A medical colloid-like composition of matter in solution comprisingthe combination of a quinicine radical and a radical of a phenoliccoloring matter.

4. A medical colloid-like composition of matter in solution comprisingthe combination of a hematoxylin radical and a quinicine radical.

5. A medical colloid-like composition of matter comprising a salt, acomponent of which is capable of causing deterioration of certainpathological cells and another component of WlllCll 1s a bmding agentfor the deteriorating agent, said colloid-like material persed conditionbeing easily hydrolyzable by said solvent to make the deterioratingagent gradually available.

In testimony whereof I hereunto afiix my signature.

ELMER H. KING.

